Long-term Integrated Safety of Patisiran in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy

Introduction Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, life-threatening disease; the majority of patients develop a mixed phenotype of polyneuropathy and cardiomyopathy. Patisiran halted or reversed polyneuropathy and improved quality of life in the Phase 3 (APOLLO) study. In a prespecified cardiac subpopulation of APOLLO, patisiran also improved cardiac structure and function versus placebo. This study aims to describe the long-term comprehensive, integrated safety data from the patisiran clinical development program in patients with hATTR amyloidosis with polyneuropathy. Hypothesis Patisiran will continue to demonstrate a positive benefit:risk profile in the integrated safety analysis. Methods Safety data as of October 7, 2019 from the Phase 2 Open-Label Extension (OLE) (NCT01961921), APOLLO (NCT01960348), and ongoing Global OLE (NCT02510261) studies were analyzed. Results Across the three studies, 224 patients received patisiran for a mean (range) of 43.6 (0.7-71.7) months, with a cumulative 813.9 patient-years of exposure; 105 (46.9%) patients received patisiran for ≥4 years and 35 (15.6%) patients received patisiran for ≥5 years. In this cohort, 149 (66.5%) had medical histories of cardiac disorders per MedDRA System Organ Class, which may be reflective of a mixed phenotype in some patients. A total of 222 (99.1%) patients experienced at least one adverse event (AE) and 132 (58.9%) patients experienced at least one serious AE. AEs considered to be related to patisiran and occurring in >5% of patients included infusion-related reactions (25.9%) and diarrhea (6.3%). Cardiac AEs occurring in >5% of patients included atrial fibrillation (10.7%) and cardiac failure (7.6%). Amongst all patients, the exposure-adjusted mortality rate was 4.3 deaths per 100 patient-years, which is on the lower end of the expected mortality rates of 6.8-29 deaths per 100 patient-years reported in the literature. Conclusions Patients with hATTR amyloidosis with polyneuropathy in the patisiran clinical development program represent those with the longest treatment with an RNAi therapeutic, including more than 15% of patients receiving patisiran for ≥5 years. Patisiran continues to demonstrate a positive benefit:risk profile in these patients.